Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM^+/−) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM^+/− mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM^+/− mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM^+/− mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm^+/− mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm^+/− mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm^+/− mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM^+/− mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

In the United States, the incidence rate of mesothelioma varies between fewer than one case per 100,000 persons in states with no asbestos industry to two to three cases per 100,000 persons in states with an asbestos industry (1, 2). Asbestos causes DNA damage and apoptosis (3) and promotes a chronic inflammatory reaction that supports the emergence of malignant cells (4). Fortunately, only a small fraction of exposed individuals develop mesothelioma; for example, 4.6% of deaths in miners who worked in asbestos mines for over 10 y were caused by mesothelioma (1). Therefore, multiple cases of mesothelioma in the same family are rare and suggest genetic predisposition (5). In 2001, we discovered that susceptibility to mesothelioma was transmitted in a Mendelian fashion across multiple generations in some Turkish families exposed to the carcinogenic fiber erionite, pointing to gene × environment interaction (G×E) as the cause (6). In 2011, we discovered that carriers of heterozygous germline BRCA1-associated protein–1 (BAP1) mutations (BAP1^+/−) developed mesothelioma and uveal melanoma (5), findings expanded and confirmed by us and by multiple research teams (reviewed in refs. 1, 7, 8). Moreover, heterozygous germline Bap1 mutations (Bap1^+/−) significantly increased susceptibility to asbestos-induced mesothelioma in mice (9, 10), evidence of G×E. Reduced BAP1 levels impair DNA repair (11) as well as different forms of cell death (3, 12) and induce metabolic alterations (13–15) that together favor cancer development and growth.Recent studies revealed that mesothelioma may also develop among carriers of germline mutations of additional tumor-suppressor genes that cause well-defined cancer syndromes, including MLH1 and MLH3 (Lynch syndrome), TP53 (Li–Fraumeni syndrome), and BRCA1-2 (Breast and Ovarian Cancer syndrome) (16, 17). When all germline mutations are combined, it has been estimated that about 12% of mesotheliomas occur in carriers of heterozygous germline mutations of BAP1, the most frequent mutation among patients with mesothelioma, or of other tumor suppressors. Some of these mutations may sensitize the host to asbestos carcinogenesis, according to a G×E scenario (17). Thus, presently, mesothelioma is considered an ideal model to study G×E in cancer (17). As part of the Healthy Nevada Project (HNP), we are studying G×E in northern Nevada, a region with an unusually high risk of exposure to carcinogenic minerals and arsenic, which may be related to the high cancer rates in this region (18). We are investigating genetic variants that may increase cancer risk upon exposure to carcinogens to implement preventive strategies.Biallelic mutations of the Bloom syndrome gene (BLM) cause Bloom syndrome, an autosomal-recessive tumor predisposition syndrome characterized by pre- and postnatal growth deficiency, photosensitivity, type 2 diabetes, and greatly increased risk of developing various types of cancers. BLM is a RecQ helicase enzyme that modulates DNA replication and repair of DNA damage by homologous recombination (19). In patients affected by Bloom syndrome, the absence of the BLM protein causes chromosomal instability, increased number of sister chromatid exchanges, and increased numbers of micronuclei (20–22). In addition, BLM is required for p53-mediated apoptosis (23), a process critical to eliminate cells that have accumulated DNA damage. Impaired DNA repair together with altered apoptosis resulted in increased cancer incidence (17, 24). Of course, inactivating germline BLM heterozygous (BLM^+/−) mutations are much more common than biallelic BLM (BLM^−/−) mutations, with an estimated frequency in the general population of 1 in 900 based on data from the Exome Aggregation Consortium (25). BLM^+/− mutation carriers do not show an obvious phenotype; however, some studies have suggested that carriers of these mutations may have an increased cancer risk (17, 24). Mice carrying Blm^+/− mutations are prone to develop a higher rate of malignancies in the presence of contributing factors, such as concurrent heterozygous mutations of the adenomatous polyposis coli (Apc) gene, or upon infection with murine leukemia virus (26). However, in studies in which Blm^+/− mice were crossed with tuberous sclerosis 1-deficient (Tsc1^+/−) mice that are predisposed to renal cystadenomas and carcinomas, Wilson et al. found that Tsc1^+/− Blm^+/− mice did not show significantly more renal cell carcinomas compared with Tsc1^+/− Blm^WT mice (27). In humans, a large study involving 1,244 patients with colon cancer and 1,839 controls of Ashkenazi Jewish ancestry, in which BLM^+/− frequency is as high as 1 in 100 individuals (28), suggested that carriers of germline BLM^+/− mutations might have a twofold increase in colorectal cancer (CRC) (29). A smaller study did not confirm these results, but reported a trend of increasing incidence of adenomas—premalignant lesions—among BLM^+/− mutation carriers (30). In addition, BLM^+/− mutations were found overrepresented among early-onset (<45 y old) CRC patients (25). Other studies associated BLM^+/− mutations to an increased risk of breast (31, 32) and prostate cancer (33), but the low power of these studies hampered definite conclusions. In summary, it appears possible that BLM^+/− mutations may increase cancer risk in the presence of contributing factors.     

Laparoendoscopic single‐site (LESS) vs laparoscopic living‐donor nephrectomy: a systematic review and meta‐analysis

The aim of this study was to provide a systematic review and meta‐analysis of reports comparing laparoendoscopic single‐site (LESS) living‐donor nephrectomy (LDN) vs standard laparoscopic LDN (LLDN). A systematic review of the literature was performed in September 2013 using PubMed, Scopus, Ovid and The Cochrane library databases. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta‐analyses criteria. Weighted mean differences (WMDs) were used to measure continuous variables and odds ratios (ORs) to measure categorical ones. Nine publications meeting eligibility criteria were identified, including 461 LESS LDN and 1006 LLDN cases. There were more left‐side cases in the LESS LDN group (96.5% vs 88.6%, P < 0.001). Meta‐analysis of extractable data showed that LLDN had a shorter operative time (WMD 15.06 min, 95% confidence interval [CI] 4.9–25.1; P = 0.003), without a significant difference in warm ischaemia time (WMD 0.41 min, 95% CI –0.02 to 0.84; P = 0.06). Estimated blood loss was lower for LESS LDN (WMD ?22.09 mL, 95% CI –29.5 to –14.6; P < 0.001); however, this difference was not clinically significant. There was a greater likelihood of conversion for LESS LDN (OR 13.21, 95% CI 4.65–37.53; P < 0.001). Hospital stay was similar (WMD –0.11 days, 95% CI –0.33 to 0.12; P = 0.35), as well as the visual analogue pain score at discharge (WMD –0.31, 95% CI –0.96 to 0.35; P = 0.36), but the analgesic requirement was lower for LESS LDN (WMD –2.58 mg, 95% CI –5.01 to –0.15; P = 0.04). Moreover, there was no difference in the postoperative complication rate (OR 1.00, 95% CI 0.65–1.54; P = 0.99). Renal function of the recipient, as based on creatinine levels at 1 month, showed similar outcomes between groups (WMD 0.10 mg/dL, –0.09 to 0.29; P = 0.29). In conclusion, LESS LDN represents an emerging option for living kidney donation. This procedure offers comparable surgical and early functional outcomes to the conventional LLDN, with a lower analgesic requirement. However, it is more technically challenging than LLDN, as shown by a greater likelihood of conversion. The role of LESS LDN remains to be defined.     

Indications for eye removal surgeries: A 15-year experience at a tertiary military hospital

Objectives:

To analyze the indications and types of eye removals at a military tertiary care hospital in Turkey.

Methods:

The medical records (age, gender, affected eye, type of surgical procedure, indications of surgery) of 123 patients who underwent evisceration and enucleation in the course of a 15-year period (January 2000 to December 2014) at Gulhane Military Medical Academy, Ankara, Turkey were reviewed retrospectively.

Results:

The mean age was 35.61±18.52 (range 3-80 years). The number of male in the patient group was 92 (74.8%) and female was 31 (25.2%). Patients who underwent evisceration were 95 (77.2%), whereas 28 (22.8%) of them underwent enucleation. The mean age of the eviscerated patients was 30.63±13.08, whereas the mean age of the enucleated patients was 52.50±23.92 (p<0.001). The leading indications for eye amputations were trauma (n=62, 50.4%), malignancy (n=20, 16.3%), painful blind eye and absolute glaucoma (n=20, 16.3%), endophthalmitis (n=12, 9.7%), and phthisis bulbi, and cosmetic reasons (n=9, 7.3%).

Conclusion:

Trauma was the most common etiology for evisceration, and malignancy was the most common etiology for enucleation. Using protective eyewear and early detection of intraocular malignancy and glaucoma through routine ophthalmic examinations are essential for providing non-invasive treatment modalities instead of eye removal.Eye removals are performed in cases of severe trauma, eye malignancy, endophthalmitis unresponsive to medical treatment, painful blind eye, and absolute glaucoma, as well as phthisic eyes with severe cosmetic defects.1-4 Evisceration is the removal of intraocular structures other than the sclera, whereas enucleation is the removal of the entire eyeball including the sclera leaving behind only the orbital structures.5 Evisceration surgery is usually preferred in extremely severe trauma cases, while enucleation is used in advanced cases of intraocular malignancy.1,3,6 The aim in such surgeries is to remove the damaged eye, provide sufficient comfort, replace the lost volume, and renew functional and cosmetic appearance.7 Removal is a difficult decision for both patients and physicians, and is considered as the last resort. In addition to clinical indications, the potential sight of the eye and patient’s psychological aspects should also be taken into consideration.1 In developed countries, the most common reasons for eye amputations are malignancy3 and trauma,6 whereas in developing countries, infections are the dominating factors.1,8 In this study, the etiology and surgery methods of 123 eye amputations performed in the Gulhane Military Medical Academy (GATA) between January 2000 and December 2014 were analyzed, and possible public health and preventive programs regarding this matter were evaluated.     

Xanthoma disseminatum: a child with respiratory system involvement and bronchiectasis

Xanthoma disseminatum (XD) is a rare normolipemic mucocutaneous xanthomatosis due to the proliferation of non-x histiocytes. Occasional involvement of the upper respiratory system has been reported, but lower respiratory tract involvement is very rare. Here, we present a child with severe involvement of the upper and lower respiratory tract by XD and bronchiectasis in the lower lobes of both lungs. The patient was an 8-year-old boy who was admitted to our hospital because of red-brown papules which developed on the skin and progressive dyspnea. He was diagnosed as having XD by skin biopsy. Physical examination revealed disseminated, numerous yellow-reddish brown papular xanthomas on the forehead and eyelids, around the neck and axillary area, and in the oral cavity and pharynx. He had respiratory distress and clubbing of the fingers. Chest x-rays showed hyperaeration and segmental atelectasis. High-resolution CT of the thorax revealed diffuse thickening of the whole tracheal and bronchial wall, and bronchiectasis in the lower lobes. Flexible fiberoptic bronchoscopy revealed numerous xanthomatous lesions in the nasal cavity, nasopharynx, oropharynx, subglottic area, trachea, bifurcation, both main bronchi, and smaller bronchi. To the best of our knowledge, this is the first report of a child with typical lesions of XD with severe involvement of the lower respiratory tract and bronchiectasis.     

The effects of very early mirror therapy on functional improvement of the upper extremity in acute stroke patients

[Purpose] The aim of the study was to evaluate the effects of a very early mirror therapy program on functional improvement of the upper extremity in acute stroke patients. [Subjects] Eight stroke patients who were treated in an acute neurology unit were included in the study. [Methods] The patients were assigned alternatively to either the mirror therapy group receiving mirror therapy and neurodevelopmental treatment or the neurodevelopmental treatment only group. The primary outcome measures were the upper extremity motor subscale of the Fugl-Meyer Assessment, Motricity Index upper extremity score, and the Stroke Upper Limb Capacity Scale. Somatosensory assessment with the Ayres Southern California Sensory Integration Test, and the Barthel Index were used as secondary outcome measures. [Results] No statistically significant improvements were found for any measures in either group after the treatment. In terms of minimally clinically important differences, there were improvements in Fugl-Meyer Assessment and Barthel Index in both mirror therapy and neurodevelopmental treatment groups. [Conclusion] The results of this pilot study revealed that very early mirror therapy has no additional effect on functional improvement of upper extremity function in acute stroke patients. Multicenter trials are needed to determine the results of early application of mirror therapy in stroke rehabilitation.Key words: Acute stroke, Mirror therapy, Upper extremity